Validation of a single-pass surgical trajectory to enable AAV2-hAADC infusion into brainstem and mid-brain in nonhuman primate

验证单次手术轨迹，使 AAV2-hAADC 能够输注到非人灵长类动物的脑干和中脑

• 批准号: 10040048
• 负责人: Krystof S Bankiewicz
• 金额: $ 42.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040048
• 关键词: 3-Dimensional; Ablation; Acids; Adverse effects; Adverse event; Affect; Amino Acids; Annual Reports; Area; Awareness; Basal Ganglia; Bilateral; Biochemical; Brain; Brain Diseases; Brain Stem; Cannulas; Carboxy-Lyases; Caregivers; Cell Nucleus; Child; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Cohort Analysis; DOPA decarboxylase; Data; Deficiency Diseases; Deposition; Disease; Dopamine; Dopamine Agonists; Dyskinetic syndrome; Dystonia; Emotional; Enzymes; Evaluation; Gene Delivery; Gene Expression; Genes; Genetic Diseases; Goals; Homovanillic Acid; Human; Hydroxyindoleacetic Acid; Hypokinesia; Impaired cognition; Impairment; Infusion procedures; Inherited; Intervention; Levodopa; Life; Limbic System; Medical; Midbrain structure; Muscle hypotonia; Mutation; Neurologic; Neurologic Symptoms; Neurotransmitters; Norepinephrine; Operative Surgical Procedures; Outcome Study; Pathologic; Pathway interactions; Patients; Procedures; Protocols documentation; Public Health; Research; Safety; Serious Adverse Event; Serotonin; Site; Sleep disturbances; Societies; Structure; Substantia nigra structure; Symptoms; System; Testing; Therapeutic; Time; Treatment Efficacy; Validation; Ventral Tegmental Area; Viral Vector; Writing; aromatic L-amino acid decarboxylase deficiency; base; burden of illness; cohort; cost; dorsal raphe nucleus; experimental study; gene therapy; improved; loss of function mutation; monoamine; motor symptom; nervous system disorder; nonhuman primate; noradrenergic; pars compacta; programs; recessive genetic trait; recruit; vector

PROJECT SUMMARY/ABSTRACT Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric genetic disorder in which mutations in the DOPA decarboxylase gene (DDC) result in a non-functional AADC enzyme that causes the ablation of dopamine and serotonin synthesis. Affected children suffer prominent motor symptoms, including hypokinesia, hypotonia, oculogyric crises and dystonia, as well as emotional lability, sleep disturbance and cognitive impairment. Patients derive little symptomatic benefit from currently available medical therapies. Our long-term goal is to provide a therapeutic approach to eliminate the neurological signs and symptoms of the disease by increasing the AADC levels via localized infusion of a viral vector (AAV2) encoding human AADC into affected nuclei in the brain. In our current exploratory clinical study (NCT02852213), we have treated 9 patients with AADC deficiency with a single bilateral infusion into the pre-nigral region to restore normal dopamine synthesis in the basal ganglia and limbic system. Preliminary evaluations from cohorts 1 and 2 have proven this approach to be safe with only mild and transient dyskinesia about one month and a half after surgery. Marked reduction or elimination of oculogyric crises has been observed. Biochemical analyses showed an increase in dopamine metabolite homovanillic acid (HVA), a slight reduction of 3-oxymethyldopa (3-OMD) while serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) remained unchanged in all patients. Currently, analyses of these cohorts, 24 and 12 months after surgery respectively, also showed that there have been no adverse events or serious adverse events related to the surgical procedure or the vector. The present proposal seeks to accumulate safety data in nonhuman primates in which a single cannula pass will enable vector delivery into serotonergic and noradrenergic nuclei as well as the current dopaminergic nuclei. Data from this study will be used to submit a new IND and recruit more patients for this new procedure. In our view, the proposed research will have a significant impact on public health. Although AADC deficiency is a rare pediatric disease, the burden to caregivers and the cost to society is large over the life of the patients not to mention the plight of the patients themselves. In the larger sense, projects like this will continue to enhance our ability to treat inherited neurological diseases.

项目概要/摘要 芳香族 L-氨基酸脱羧酶 (AADC) 缺乏症是一种罕见的儿科遗传性疾病，其中突变 多巴脱羧酶基因 (DDC) 中的多巴脱羧酶基因 (DDC) 会产生无功能的 AADC 酶，从而导致 多巴胺和血清素的合成。受影响的儿童会出现明显的运动症状，包括运动功能减退、 肌张力低下、眼部危机和肌张力障碍，以及情绪不稳定、睡眠障碍和认知障碍 损害。患者从目前可用的药物治疗中获得的症状很少。我们的长期 目标是提供一种治疗方法，通过以下方式消除疾病的神经体征和症状： 通过将编码人 AADC 的病毒载体 (AAV2) 局部输注至受影响的患者体内，提高 AADC 水平 大脑中的细胞核。在我们目前的探索性临床研究 (NCT02852213) 中，我们治疗了 9 名患者 AADC 缺乏症可通过单次双侧输注至黑前区域恢复正常的多巴胺合成 在基底神经节和边缘系统中。第 1 组和第 2 组的初步评估证明了这一点 这种方法是安全的，仅在术后一个半月左右出现轻微和短暂的运动障碍。标记 已观察到眼部危机的减少或消除。生化分析显示， 多巴胺代谢物高香草酸 (HVA)，轻微减少 3-羟甲基多巴 (3-OMD)，同时血清素 所有患者的代谢物 5-羟基吲哚乙酸 (5-HIAA) 均保持不变。目前，对这些 分别在手术后 24 个月和 12 个月的队列也表明没有出现不良事件或 与外科手术或载体相关的严重不良事件。 本提案旨在积累非人类灵长类动物的安全数据，其中单个插管通过即可 使载体能够递送至血清素能和去甲肾上腺素能核以及当前的多巴胺能核。 这项研究的数据将用于提交新的 IND 并招募更多患者进行这项新手术。 我们认为，拟议的研究将对公众健康产生重大影响。尽管 AADC 缺乏 这是一种罕见的儿科疾病，在患者的一生中，护理人员的负担和社会成本都很大 更不用说患者本身的困境了。从更大的意义上讲，此类项目将继续增强 我们治疗遗传性神经系统疾病的能力。